Cognate CD4 T-cell licensing of dendritic cells heralds anti-CMV CD8 T-cell immunity after human allogeneic umbilical cord blood transplantation

Abstract

Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord-blood transplantation (CBT), lowering survival rates by approximately 25%. While antiviral treatment ameliorates viremia, complete viral control requires CD8(+) T-cell-driven immunity. Mouse studies suggest that cognate antigen-specific CD4(+) T-cell licensing of dendritic cells is required to generate effective CD8(+) T-cell responses. For humans this was not fully understood. We here show that CD4(+) T-cells are essential for licensing of human DCs to generate effector and memory CD8(+) T-cell immunity against CMV in CBT patients. First, we show in CBT recipients that clonal expansion of CMV-pp65 specific CD4(+) T-cells precedes the rise in CMV-pp65 specific CD8(+) T-cells. Second, the elicitation of CMV-pp65 specific CD8(+) T-cells from rare naïve precursors in cord blood requires DC licensing by cognate CMV-pp65-specific CD4(+) T-cells. Finally, also CD8(+) T-cell memory responses require CD4(+) T-cell-mediated licensing of DCs in our system, by secretion of IFN-γ by pp65-specific CD4(+) T-cells. Together these data show that human DCs require the licensing by cognate antigen-specific CD4(+) T-cells to elicit effective CD8(+) T-cell-mediated immunity and fight off viral reactivation in CBT patients. IMPORTANCE PARAGRAPH: Survival rates after stem cell transplantation are lowered by 25% when patients undergo reactivation of cytomegalovirus (CMV) they harbor. Immune protection against CMV is mostly executed by white blood cells called killer T-cells. We here show that for generation of optimally protective killer T-cell responses that respond to CMV, the early elicitation of help from a second branch of CMV-directed T-cells, called helper T-cells, is required.